Viorica Chelban

A genome-wide association study in multiple system atrophy

Objective: To identify genetic variants that play a role in the pathogenesis of multiple system atrophy (MSA), we undertook a genome-wide association study (GWAS). Methods: We performed a GWAS with >5 million genotyped and imputed single nucleotide polymorphisms (SNPs) in 918 patients with MSA of European ancestry and 3,864 controls. MSA cases were collected from North American and European centers, one third of which were neuropathologically confirmed. Results: We found no significant loci after stringent multiple testing correction. A number of regions emerged as potentially interesting for follow-up at p < 1 × 10−6, including SNPs in the genes FBXO47, ELOVL7, EDN1, and MAPT. Contrary to previous reports, we found no association of the genes SNCA and COQ2 with MSA. Conclusions: We present a GWAS in MSA. We have identified several potentially interesting gene loci, including the MAPT locus, whose significance will have to be evaluated in a larger sample set. Common genetic variation in SNCA and COQ2 does not seem to be associated with MSA. In the future, additional samples of well-characterized patients with MSA will need to be collected to perform a larger MSA GWAS, but this initial study forms the basis for these next steps.

Genetic and phenotypic characterization of complex hereditary spastic paraplegia

High-throughput next-generation sequencing can identify disease-causing mutations in extremely heterogeneous disorders. Kara et al . investigate a series of 97 index cases with complex hereditary spastic paraplegia (HSP). They identify SPG11 defects in 30 families, as well as mutations in other HSP genes and genes associated with disorders including Parkinson’s disease.

Mutations in NKX6-2 Cause Progressive Spastic Ataxia and Hypomyelination.

Progressive limb spasticity and cerebellar ataxia are frequently found together in clinical practice and form a heterogeneous group of degenerative disorders that are classified either as pure spastic ataxia or as complex spastic ataxia with additional neurological signs. Inheritance is either autosomal dominant or autosomal recessive. Hypomyelinating features on MRI are sometimes seen with spastic ataxia, but this is usually mild in adults and severe and life limiting in children. We report seven individuals with an early-onset spastic-ataxia phenotype. The individuals come from three families of different ethnic backgrounds. Affected members of two families had childhood onset disease with very slow progression. They are still alive in their 30s and 40s and show predominant ataxia and cerebellar atrophy features on imaging. Affected members of the third family had a similar but earlier-onset presentation associated with brain hypomyelination. Using a combination of homozygozity mapping and exome sequencing, we mapped this phenotype to deleterious nonsense or homeobox domain missense mutations in NKX6-2. NKX6-2 encodes a transcriptional repressor with early high general and late focused CNS expression. Deficiency of its mouse ortholog results in widespread hypomyelination in the brain and optic nerve, as well as in poor motor coordination in a pattern consistent with the observed human phenotype. In-silico analysis of human brain expression and network data provides evidence that NKX6-2 is involved in oligodendrocyte maturation and might act within the same pathways of genes already associated with central hypomyelination. Our results support a non-redundant developmental role of NKX6-2 in humans and imply that NKX6-2 mutations should be considered in the differential diagnosis of spastic ataxia and hypomyelination.

Genotype-phenotype correlations and expansion of the molecular spectrum of AP4M1-related hereditary spastic paraplegia

BackgroundAutosomal recessive hereditary spastic paraplegia (HSP) due to AP4M1 mutations is a very rare neurodevelopmental disorder reported for only a few patients.MethodsWe investigated a Greek HSP family using whole exome sequencing (WES).ResultsA novel AP4M1A frameshift insertion, and a very rare missense variant were identified in all three affected siblings in the compound heterozygous state (p.V174fs and p.C319R); the unaffected parents were carriers of only one variant. Patients were affected with a combination of: (a) febrile seizures with onset in the first year of life (followed by epileptic non-febrile seizures); (b) distinctive facial appearance (e.g., coarse features, bulbous nose and hypomimia); (c) developmental delay and intellectual disability; (d) early-onset spastic weakness of the lower limbs; and (e) cerebellar hypoplasia/atrophy on brain MRI.ConclusionsWe review genotype-phenotype correlations and discuss clinical overlaps between different AP4-related diseases. The AP4M1 belongs to a complex that mediates vesicle trafficking of glutamate receptors, being likely involved in brain development and neurotransmission.

Severe axonal neuropathy is a late manifestation of SPG11

Complex hereditary spastic paraplegia (HSP) is a clinically heterogeneous group of disorders usually inherited in an autosomal recessive manner. In the past, complex recessive spastic paraplegias have been frequently associated with SPG11 mutations but also with defects in SPG15, SPG7 and a handful of other rare genes. Pleiotropy exists in HSP genes, exemplified in the recent association of SPG11 mutations with CMT2. In this study, we performed whole exome sequence analysis and identified two siblings with novel compound heterozygous frameshift SPG11 mutations. The mutations segregated with disease were not present in control databases and analysis of skin fibroblast derived mRNA indicated that the SPG11 truncated mRNA species were not degraded significantly by non-sense mediated mRNA decay. These siblings had severe early-onset spastic paraplegia but later in their disease developed severe axonal neuropathy, neuropathic pain and blue/black foot discolouration likely caused by a combination of the severe neuropathy with autonomic dysfunction and peripheral oedema. We also identified a similar late-onset axonal neuropathy in a Cypriot SPG11 family. Although neuropathy is occasionally present in SPG11, in our SPG11 patients reported here it was particularly severe, highlighting the association of axonal neuropathy with SPG11 and the late manifestation of axonal peripheral nerve damage.

Autonomic dysfunction in genetic forms of synucleinopathies: Autonomic Dysfunction in Synucleinopathies

The discovery of genetic links between alpha‐synuclein and PD has opened unprecedented opportunities for research into a new group of diseases, now collectively known as synucleinopathies. Autonomic dysfunction, including cardiac sympathetic denervation, has been reported in familial forms of synucleinopathies that have Lewy bodies at the core of their pathogenesis. SNCA mutations and multiplications, LRRK2 disease with Lewy bodies as well as other common, sporadic forms of idiopathic PD, MSA, pure autonomic failure, and dementia with Lewy bodies have all been associated with dysautonomia. By contrast, in familial cases of parkinsonism without Lewy bodies, such as in PARK2, the autonomic profile remains normal throughout the course of the disease. The degeneration of the central and peripheral autonomic systems in genetic as well as sporadic forms of neurodegenerative synucleinopathies correlates with the accumulation of alpha‐synuclein immunoreactive‐containing inclusions. Given that dysautonomia has a significant impact on the quality of life of sufferers and autonomic symptoms are generally treatable, a prompt diagnostic testing and treatment should be provided. Moreover, new evidence suggests that autonomic dysfunction can be used as an outcome prediction factor in some forms of synucleinopathies or premotor diagnostic markers that could be used in the future to define further research avenues. In this review, we describe the autonomic dysfunction of genetic synucleinopathies in comparison to the dysautonomia of sporadic forms of alpha‐synuclein accumulation and provide the reader with an up‐to‐date overview of the current understanding in this fast‐growing field.

Genotype-phenotype correlations, dystonia and disease progression in spinocerebellar ataxia type 14

Background: Spinocerebellar ataxia type 14 is a rare form of autosomal dominant cerebellar ataxia caused by mutations in protein kinase Cγ gene. Clinically, it presents with a slowly progressive, mainly pure cerebellar ataxia.

Truncating mutations in SPAST patients are associated with a high rate of psychiatric comorbidities in hereditary spastic paraplegia

Background The hereditary spastic paraplegias (HSPs) are a rare and heterogeneous group of neurodegenerative disorders that are clinically characterised by progressive lower limb spasticity. They are classified as either ‘pure’ or ‘complex’ where spastic paraplegia is complicated with additional neurological features. Mutations in the spastin gene (SPAST) are the most common cause of HSP and typically present with a pure form. Methods We assessed in detail the phenotypic and genetic spectrum of SPAST-related HSP focused on 118 patients carrying SPAST mutations. Results This study, one of the largest cohorts of genetically confirmed spastin patients to date, contributes with the discovery of a significant number of novel SPAST mutations. Our data reveal a high rate of complex cases (25%), with psychiatric disorders among the most common comorbidity (10% of all SPASTpatients). Further, we identify a genotype–phenotype correlation between patients carrying loss-of-function mutations in SPAST and the presence of psychiatric disorders.

Triple trouble: a striking new phenotype or competing genes in a family with hereditary spastic paraplegia.

The term hereditary spastic paraplegia (HSP) describes a number of genetically heterogeneous diseases leading to slowly progressive lower limb spasticity and weakness. It is divided into pure and complex types, according to clinical signs and involved genes. Mutations in SPAST are the most frequent cause of autosomal dominant (AD) pure HSP, and symptoms are typically confined to lower limb spasticity and urinary urgency [1]. We describe 2 brothers, both of whom presented with progressive lower limb spasticity, in whom later symptoms challenged the paradigm of SPAST-related pure HSP, but were ultimately found to each carry different mutations in 2 unrelated genes. The first patient (case III-6) presented at age 24 years with progressive gait disturbance and lower limb spasticity. Clinical examination revealed increased tone, pyramidal weakness, brisk reflexes and extensor plantar responses. There was a family history of similar walking problems in his mother and maternal grandfather, suggesting autosomal dominant (AD) inheritance. Sequence analysis of SPAST gene revealed the heterozygous pathogenic mutation c.1082C[T; p.P361 present in the patient and his affected mother. In the following years, the spasticity progressed reaching an Ashworth score (AS) of 3/4 in plantarflexion and dorsiflexion with fixed deformities at the ankle. At the age of 40 years, now 15 years after onset of symptoms, the patient began to develop slowly progressive ptosis, ophthalmoplegia and dysphagia. These symptoms have been described in patients with complex HSP due to mutations in SPG7 and SPG11 [2], but not in patients with pure HSP due to SPAST mutations. This new phenotype prompted a re-discussion of family history and revealed a similar history in the patient’s father, paternal grandfather and other relatives which had previously been withheld by the family. Testing of the PABPNI gene, responsible for oculopharyngeal muscular dystrophy (OPMD), revealed the presence of a heterozygous triplet expansion of 14 repeats, confirming the dual diagnosis of HSP and OPMD (Fig. 1). Surprisingly, as the ptosis and dysphagia progressed there was a mild improvement in the spasticity. At last clinical examination, 30 years after the onset of HSP, the proband presented with a typical OPMD phenotype with ptosis requiring tarsorrhaphy, ophtalmoplegia and dysphagia complicated by distal muscle wasting and spastic paraplegia in the lower limbs. The patient’s brother, case III-5, presented with slowly progressive spastic paraplegia and tiptoe walking with insidious onset in childhood. Clinical examination findings were similar to his brother, with lower limb spasticity, brisk reflexes and extensor plantars. He was also found to carry the c.1082C[T; p.P361L SPAST mutation. He did not carry an expanded PABPNI allele. However, clinical examination did reveal a dark complexion with multiple hyper-pigmented areas, café-au-lait spots and multiple subcutaneous submobile lesions. A skin biopsy confirmed the presence of neurofibroma. The patient met & Viorica Chelban v.chelban@ucl.ac.uk

Lysosomal storage disorder gene variants in multiple system atrophy

1. Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK 2. National Hospital for Neurology and Neurosurgery, Queen Square, London, UK 3. Oslo University Hospital, Oslo, Norway. 4. French Reference Center for MSA, Department of Neurology, University Hospital Bordeaux, 33000 Bordeaux and Institute of Neurodegenerative Diseases, CNRS UMR 5293, University Bordeaux, 33000 Bordeaux, France. 5. Laboratory of Neurogenetics, NIH/NIA, Bethesda, USA. * h.houlden@ucl.ac.uk